title: Carrier detection in a partially dominant X-linked disease: ornithine transcarbamylase deficiency.
abstract: Ornithine transcarbamylase (OTC) deficiency is an X-linked disease responsible for lethal neonatal hyperammonemia in males. Partial OTC deficiency also occurs in females and can be responsible for life-threatening hyperammonemic comas in heterozygotes (15%). Increased orotic acid excretion occurs in both symptomatic and asymptomatic carriers, especially under protein loading tests. The disease is therefore partially dominant with neonatal lethality in the hemizygous male; the fraction of new mutations has previously been estimated to be low in males (point estimation = 0, upper bound of the confidence interval = 0.16) and 57% in females. Genetic counseling in this disease is difficult because it is not clear whether a negative protein loading test rules out carrier status. In an attempt to determine how reliable the test is for carrier detection, we investigated ten obligate carriers for orotic acid excretion; considering all data available, we concluded that the test is rarely negative in obligate carriers (8%). Consequently, a negative test in a mother decreases the minimum risk of being a carrier from 84% a priori to 30% if she had an affected son and from 43% a priori to 5% if she had a heterozygous daughter. Finally, the diagnosis of a new mutation in the germ cells of the maternal grandfather in one particular family could be ascertained by extensive DNA analysis.
authors.affiliation: Unité de Recherches de Génétique Médicale INSERUM U. 12, Hôpital des Enfants-Malades, Paris, France.
authors.forename: A
authors.initials: A
authors.lastname: Pelet
authors.forename: A
authors.initials: A
authors.lastname: Rotig
authors.forename: C
authors.initials: C
authors.lastname: Bonaïti-Pellié
authors.forename: D
authors.initials: D
authors.lastname: Rabier
authors.forename: V
authors.initials: V
authors.lastname: Cormier
authors.forename: E
authors.initials: E
authors.lastname: Toumas
authors.forename: D
authors.initials: D
authors.lastname: Hentzen
authors.forename: J M
authors.initials: JM
authors.lastname: Saudubray
authors.forename: A
authors.initials: A
authors.lastname: Munnich
mesh_terms: D001499:Bayes Theorem; D005260:Female; D006580:Genetic Carrier Screening; D008040:Genetic Linkage; D006801:Humans; D008297:Male; D009154:Mutation; D009954:Ornithine Carbamoyltransferase / Q000235:genetics; D020163:Ornithine Carbamoyltransferase Deficiency Disease; D009963:Orotic Acid / Q000652:urine; D010375:Pedigree; D014960:X Chromosome
chemical_list: D009963:Orotic Acid; D009954:Ornithine Carbamoyltransferase